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Tasquinimod Is an Allosteric Modulator of HDAC4 Survival Signaling within the Compromised Cancer Microenvironment

Isaacs, John T. ; Antony, Lizamma ; Dalrymple, Susan L. ; Brennen, W. Nathaniel ; Gerber, Stephanie ; Hammers, Hans ; Wissing, Michel ; Kachhap, Sushant ; Luo, Jun and Xing, Li , et al. (2013) In Cancer Research 74(4). p.1386-1399
Abstract
Tasquinimod is an orally active antiangiogenic drug that is currently in phase III clinical trials for the treatment of castration-resistant prostate cancer. However, the target of this drug has remained unclear. In this study, we applied diverse strategies to identify the histone deacetylase HDAC4 as a target for the antiangiogenic activity of tasquinimod. Our comprehensive analysis revealed allosteric binding (Kd 10-30 nmol/L) to the regulatory Zn2+ binding domain of HDAC4 that locks the protein in a conformation preventing HDAC4/N-CoR/HDAC3 complex formation. This binding inhibited colocalization of N-CoR/HDAC3, thereby inhibiting deacetylation of histones and HDAC4 client transcription factors, such as HIF-1 alpha, which are bound at... (More)
Tasquinimod is an orally active antiangiogenic drug that is currently in phase III clinical trials for the treatment of castration-resistant prostate cancer. However, the target of this drug has remained unclear. In this study, we applied diverse strategies to identify the histone deacetylase HDAC4 as a target for the antiangiogenic activity of tasquinimod. Our comprehensive analysis revealed allosteric binding (Kd 10-30 nmol/L) to the regulatory Zn2+ binding domain of HDAC4 that locks the protein in a conformation preventing HDAC4/N-CoR/HDAC3 complex formation. This binding inhibited colocalization of N-CoR/HDAC3, thereby inhibiting deacetylation of histones and HDAC4 client transcription factors, such as HIF-1 alpha, which are bound at promoter/enhancers where epigenetic reprogramming is required for cancer cell survival and angiogenic response. Through this mechanism, tasquinimod is effective as a monotherapeutic agent against human prostate, breast, bladder, and colon tumor xenografts, where its efficacy could be further enhanced in combination with a targeted thapsigargin prodrug (G202) that selectively kills tumor endothelial cells. Together, our findings define a mechanism of action of tasquinimod and offer a perspective on how its clinical activity might be leveraged in combination with other drugs that target the tumor microenvironment. Cancer Res; 73(4); 1386-99. (C) 2012 AACR. (Less)
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Cancer Research
volume
74
issue
4
pages
1386 - 1399
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American Association for Cancer Research Inc.
external identifiers
  • wos:000315029800013
  • scopus:84874342427
  • pmid:23149916
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1538-7445
DOI
10.1158/0008-5472.CAN-12-2730
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English
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7ec74219-66c4-4db5-9457-0d25926e0b70 (old id 3577906)
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@article{7ec74219-66c4-4db5-9457-0d25926e0b70,
  abstract     = {Tasquinimod is an orally active antiangiogenic drug that is currently in phase III clinical trials for the treatment of castration-resistant prostate cancer. However, the target of this drug has remained unclear. In this study, we applied diverse strategies to identify the histone deacetylase HDAC4 as a target for the antiangiogenic activity of tasquinimod. Our comprehensive analysis revealed allosteric binding (Kd 10-30 nmol/L) to the regulatory Zn2+ binding domain of HDAC4 that locks the protein in a conformation preventing HDAC4/N-CoR/HDAC3 complex formation. This binding inhibited colocalization of N-CoR/HDAC3, thereby inhibiting deacetylation of histones and HDAC4 client transcription factors, such as HIF-1 alpha, which are bound at promoter/enhancers where epigenetic reprogramming is required for cancer cell survival and angiogenic response. Through this mechanism, tasquinimod is effective as a monotherapeutic agent against human prostate, breast, bladder, and colon tumor xenografts, where its efficacy could be further enhanced in combination with a targeted thapsigargin prodrug (G202) that selectively kills tumor endothelial cells. Together, our findings define a mechanism of action of tasquinimod and offer a perspective on how its clinical activity might be leveraged in combination with other drugs that target the tumor microenvironment. Cancer Res; 73(4); 1386-99. (C) 2012 AACR.},
  author       = {Isaacs, John T. and Antony, Lizamma and Dalrymple, Susan L. and Brennen, W. Nathaniel and Gerber, Stephanie and Hammers, Hans and Wissing, Michel and Kachhap, Sushant and Luo, Jun and Xing, Li and Bjork, Per and Olsson, Anders and Bjork, Anders and Leanderson, Tomas},
  issn         = {1538-7445},
  language     = {eng},
  number       = {4},
  pages        = {1386--1399},
  publisher    = {American Association for Cancer Research Inc.},
  series       = {Cancer Research},
  title        = {Tasquinimod Is an Allosteric Modulator of HDAC4 Survival Signaling within the Compromised Cancer Microenvironment},
  url          = {http://dx.doi.org/10.1158/0008-5472.CAN-12-2730},
  doi          = {10.1158/0008-5472.CAN-12-2730},
  volume       = {74},
  year         = {2013},
}